1. Field of the Invention
The present invention relates to a peptide derivative comprising a tripeptide unit or a pharmaceutically acceptable salt thereof as an essential constituent unit as well as a composition for inhibiting metastasis of tumor.
2. Prior Art
Fibronectin is a protein involved in the cell-extracellular substrate cohesion and is likewise thought to be involved in coagulation of blood platelets and the metastasis of tumor. These interactions are mediated by a series of receptors present in the cell surface region, it is confirmed that these receptors can specifically recognize an amino acid sequence: arginine-glycine-aspartic acid (hereinafter abbreviated as "Arg--Gly--Asp") of the fibronectin although the fibronectin is a macromolecule having a molecular weight of about 250,000, and there has been reported that the sequence plays an important role in the interaction between the receptors and the fibronectin (Nature, 309, 1984, p 30). The above tripeptide sequence, Arg--Gly--Asp, is present in other cohesive proteins such as vitronectin, and fibronectin associates with receptors of cells via the tripeptide sequence to transfer the information of fibronection to the adhered cells. Further, fibronectin is thought to have bonding ability to natural macromolecules such as heparin, collagen and fibrin and to be involved in adhesion of cells and interstitial connective tissue as well as differentiation and proliferation of cells.
Since the proteins having the cell adhesion activity have various biological activities as described above, there have been conducted many studies on the applications of these proteins for pharmaceutical drugs and materials. For example, there have been reported a method for inhibiting the coagulation of blood platelets by the use of various linear and cyclic oligopeptides having an Arg--Gly--Asp sequence (Polymer Preprints, Japan, 38, 1989, p. 3149; Japanese Unexamined Patent Publication (hereinafter referred to as "J. P. KOKAI") No. Hei 2-174797); a method in which a peptide having an Arg--Gly--Asp sequence is used as a cell movement-inhibiting agent (J. P. KOKAI No. Hei 2-4716); and a method using, as a cell-adhesive membrane, a PMMA film on which Arg--Gly--Asp sequences are immobilized (Polymer Preprints, Japan, 37, 1988, p. 705). In addition, J. P. KOKAI Nos. Hei 1-309682 and Hei 1-305960 disclose a method which comprises covalently bonding peptides having Arg--Gly--Asp sequences as essential structural units to a polymer and in which the resulting product is used as a substrate for cultivating animal cells or for biological composite artificial organs and J. P. KOKAI No. Sho 64-6217 discloses a method in which a polypeptide having Arg--Gly--Asp--Ser (SEQ ID NO.16) sequences is used as a platelet protective agent for blood taken out of the body.
Further, the cell-adhesive proteins have been paid attention as materials involved in metastasis of tumor. During the series of stages of the metastasis of tumor, tumor cells could contact with various host cells and biological macromolecules and, by the presence of the cell adhesive proteins such as fibronectin, the cells form cell coagulations to facilitate proliferation and survival of the tumor cells. In this regard, however, it is reported that if the adhesive core sequence of fibronectin, the tripeptide Arg--Gly--Asp, is present in such a circumstance, the tripeptide would associate with the receptors on the surface of the cells in a competitive manner with the cell adhesive proteins and thus may inhibit the metastasis of tumor (Science, 238 (1986) p 467). Further, there has been known a method comprising inhibiting the metastasis of tumor by the use of an oligopeptide having Arg--Gly--Asp sequences or a polypeptide having the sequence as repeating units (Int. J. Biol. Macromol., 11, 1989, p 23 ibid, 11, 1989, p. 226; and Jpn. J. Cancer Res., 60, 1989, p. 722).
As described above, many studies on the applications of the activities of the cell adhesive proteins such as fibronectin or peptide fragments thereof for pharmaceutical drugs and related medical materials have actively conducted, and the applications of the adhesive core sequence, Arg--Gly--Asp--Ser, (SEQ ID NO.16) to tumor metastasis inhibiting agents are particularly intensively conducted. However, according to the studies so far, the core sequence was regarded as essential for the expression of the biological activity mediated by the receptor and the ligand and it was reported that any peptide analog having another amino acid residue instead of any of the constitiuent amino acid residues, particularly the Arg residue, could not exhibit the activity .(:Polymer Preprints, Japan, 38 (1989) p 3149: J. Biol. Chem., 262 (1987) p 17294).